An emerging clinical approach to treat substance abuse disorders involves a form of cognitive-behavioral therapy whereby addicts learn to reduce their reactivity to drug-paired stimuli through cue-exposure or extinction training. It is, however, unlikely that extinction training would be consistently effective as a stand- alone treatment in populations that have abused drugs long-term because the key memory systems that are recruited during extinction training are impaired by long-term drug use. There is a critical need to understand mechanisms underlying extinction learning and to establish viable strategies to increase the efficacy of extinction therapies for substance abuse disorders. Key elements of the proposed research plan build on recent advances made in the treatment of conditioned fear and anxiety and other cognitive disorders by pharmacological modulation of glycine, an obligatory co-transmitter at the NMDA glutamate receptor complex. The specific aims of the proposed research in rats and non-human primates are to: 1) elucidate the neurobiological substrates of extinction learning;2) evaluate selected glycine site partial agonists and glycine transporter-1 (GlyT1) inhibitors as candidate pharmacotherapies to increase the efficacy of extinction training;and 3) determine neurobiological substrates of glycine site modulation of extinction learning. The intravenous cocaine self-administration procedure will be used in the proposed studies because the contingency between drug delivery and behavior is likely paramount for understanding the persistent abuse of drugs in people. Measurement of Fos protein expression (a marker for neuronal activation) and evaluation with anisomycin (an inhibitor of de novo protein synthesis) will be used in rats to investigate the neurobiological substrates of extinction learning following cocaine self-administration training. In addition, the proposed research in rats and non-human primates will specifically investigate the effects of the partial glycine agonist D-cycloserine and selective GlyT1 inhibitors for their ability to accelerate extinction learning and to subsequently reduce cocaine cue reactivity and re-acquisition of cocaine self-administration. Animal research involving pharmacological modulation of learning and memory is well-served by an integrated comparative strategy using appropriately selected laboratory animals. This approach is especially relevant for research involving cognitive enhancing drugs, where non-human primates can serve as a key translational interface for the development of pharmacotherapies.